CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia

Abstract

Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion-driven leukemogenesis and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.

t(8;21) Acute Myeloid Leukemia as a Paradigm for the Understanding of Leukemogenesis at the Level of Gene Regulation and Chromatin Programming

“…Further evaluation both ex vivo in patient-derived AML cells and in vivo in immunodeficient mice transplanted with RUNX1/ETO-expressing AML cells demonstrated a high sensitivity of this AML subtype to palbociclib inhibition. Interestingly, similar findings have also been reported for AMLs expressing FLT3-ITD or another leukemic fusion protein NUP98/NSD1 [ 88 , 89 ]. Inhibition of CDK4/6 is cytostatic; ongoing research, thus, aims to identify novel drug combinations with, e.g., MTOR inhibitors or components of current chemotherapy such as cytarabine for the elimination of leukemic cells [ 90 , 91 ].…”

CDK6 Is a Potential Prognostic Biomarker in Acute Myeloid Leukemia

“…CDK6 also plays a crucial role in malignant hematopoietic tumors. It is not only required for maintenance of NUP98-fusion AML but also could act an important role in MLL (KMT2A) fusions-mediated myeloid leukemogenesis ( Schmoellerl et al, 2020 ). Some AML patients with FLT3-ITD mutation failed to induce a persistent response via FLT3 inhibitor.…”

The RUNX1/RUNX1T1 network: translating insights into therapeutic options

“…Many of the corresponding gene loci are bound by leukaemic fusion proteins and may, thus, be directly controlled by them. For instance, the CDK6 and CCND3 loci are direct target genes of MLL/AF4, the most frequent fusion protein found in infant leukaemia, and several NUP98 fusion proteins drive CDK6 transcription by binding to its promoter [5,7]. Thus, promotion of G1 cell cycle phase progression by activating CDK6 expression is a common theme for leukaemic fusion proteins (Fig.…”

“…Recently, a third class has been suggested that separates mutated epigenetic modifiers and readers from class 2. However, more recent investigations of transcriptional networks underlying the leukaemic phenotypes have blurred this clear distinction with type 2 members also promoting proliferation by controlling growth factor and cell cycle genes such as FLT3, CDK6 or CCND2 [5][6][7]. Since pre-leukaemic and leukaemic self-renewal is dependent on cells cycle progression, it is not really surprising that class 2 mutations also drive proliferation as part of their programme.…”